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461

A MULTICENTER PHASE II TRIAL WITH GEMCITABINE IN NON SMALL CELL LUNG CANCER (NSCLC) U.Garzemeier~.Shepherd,T.Le Chevalier,P.Weynants,B.Cottier,H.J.M Green, R. Rosso, K.Mattson,H.Cortes-Funes,M.Tonato,M.Voi; Krankenhaus Grosshansdorf, Germany;Toronto General Hospital,Canada;lnstihrte Gustave Roussy, France; Clinique Universitaires,U.C.L. de Mont-Godinne, Belgium: Clatterbridee Cerme for Oncoloev. U K;Academixh Ziekenhuis. Groningen, Ne&rlan&:Instita~Nazionale per la Ric&a sol C~ro,Genova, 1taly;Helsinki University Central Hospital, Finland: Hospital 12 de Octubre,Spain; Ospedale, Peru&+ Italy and Lilly Research Centre,Whrdlesham,lJK.

Gemcitabine is a novel pyrimidine analog with activity reported in a variety of solid tumors. We report here the fmal results of a multicenter phase II study of gemcitabine in patients with inoperable NSCLC. Gemcitabime was administered as a 30’ iv infusion once a week for 3 weeks followed by a week of rest which constitutes 1 cycle. AU 161 enrolled patients were evaluable for safety and 15 1 who completed at least 1 cycle of therapy were evaluable for efticacy.The majority of patients were stage IIlb (3 1%) or IV (65%) with a performance status (PS) of 1 in 83% or2 in 6%. Histology showed adenowcinomain 52% of patients and squamous in 43%. There were 3 complete and 30 wtial responses for an ovemll reswnse rate of 22% (95% C.I.: 15.5.29.3%). All re$onses w&e independently valid&h by an Oncolo~v &view Board. Median&me to response was 1.9 months with a median duration of response of 7.6 months. 64% of responders had stage IV disease; 51.5%,36.4% and 12.1% of resoonders had sauamous. . ad&o or mixed c&noma, respectively. Median time to progre’ssion was 4.6 months (3.3 months in non-responders~and 7.6 months in responders). Median sunival in all patients was 8.9 months (O-7.0 months) but with still 38.5% of censored observations 12 months after last patient started treamxnt. Median survival was 7.3 months in non-

‘responders (32.8% censored) while it was 12.4 months in responders (60.6% censored); the difference was statistically significant @<O.oOl. log-rank and Wilcoxon). No statistically significant difference in survival rates was found when comparing patients with stage Ill YS lV,age c 65 vs 2 65 yexs,PS on enny,gender or histology.Subjective improvement lasting for at least 4 weeks was seen for PS (9% of elinible mtientsl. no weight change (75.5%), reduced analgesic use (27.7%) and’& relie~(31.$%). O&r disease-related symptoms improving for 11 to 18 weeks included cough, dyspnea hemoptysis, anorexia, somnolence and hoarseness. Toxicity was mcdest:neutropenia was the most frequent dose-limiting toxicity but only 20.9% and 5.7% of the patients experienced at least 1 episode of WHO grade III or IV toxicity, respectively. The 22% externally validated response rate confums gemcitabine as one of tie most effective single agents in NSCLC. The novel mode of action of gemcitabine together with its modest toxicity warrants further studies m combination with other chemotherapy.

463

PHASE I AND PHARMACOKINETIC (PK) STUDY OF CIPOMEANOL (IPO) IN PATIENTS IPTS) WITH NON-SMALL CELL LUNG CANCER (NSCLC). M.J. Kel1ey;M.P. Dearing, M. Christian, G. Sladek, J. Phares, M. Edison, B. Kramer, B.E. Johnson. National Cancer Institute and National Naval Medical Center; Bethesda, MD, USA

IPO, a furan compound produced in moldy sweet potatoes, is a pulmonary toxin in mammals. After metabolism by a component of the &?tochrotie P450 system, IPO rapidly binds to macrdmolecul& resulting in localized toxicitv (tax). The findine of IPO activation in bronchial Clara cells ,~ , of animals has led to the diseas&xific development of IPO for lung cancer. Antitumor activity of IPO has been demonstrated in in vitro and in xenograft tumor model systems of NSCLC but not SCLC. We have treated 30 pts with NSCLC with IPO for 5 daily doses, administering a total of 47 cycles. There were 22 males and 8 females. Median age was 57 years (range 32-68). Performance status was 0 in 3 pts, 1 in 25 and 2 in 2. Predominant histologic type was adeno in 14, bronchioloalveolar in 6, large cell in 4, squamous in 2, adenosquamous in 1, and NSCLC in3. Starting dose was 35 mg/m2/d (0.1 of the LQo in mice) and maximum dose to date is 521 mg/m2/d. Dose-limiting tax has not been reached. Predominant tax to date has been asymptomatic hypertransamhusemia with grade (gr) 3 tax occurring in 2 pts (at 167 and 295 mg/mz/d) and with gr 1 or 2 tax in 5 pb. 167 mg/m2/d. Gr 1 or 2 nausea/vomitin

One pt had gr 3 pulmonary tax at

d:”

has occurred in 6 of the 8 patients treated at higher doses (295 to 521 m /m /d). prolongation of PT and PTT an

Other noted tax includes gr 1 gr 1 hematuria. All tox resolved

spontaneously. There have been no objective responses; 18 pts had stable disease lasting a median of 3 weeks (range 3-28) and 1 pt received 6 cycles. PK analysis of 15 pts from day 1 of IPO administration revealed biexponential elimination with mean half-lives of 8.9 min (a) and 70.3 tnin (p). The Vdss was 79.5 L/m* and plasma clearance rate was 1.74 L/min/m*. Renal clearance was less than 5%. At 167 mg/m2, mean Cp max is 19.7 pM and the AUC is 699 ph4min. There was no significant difference between PK parameters from day 1 and day 5. Conclusions to date from this continuing trial are: 1) although MTD has not been reached, liver tox is more predominant than long tax in humans; 2) current data indicate that a 5 daily dose schedule will allow administration of at least 2.5 times the amount of IPO per cycles compared with a single bolos dose; 3) IPO PK parameters do not change significantly with repeated daily administration; and 4) dose escalation should continue.

462

A PHASE l/II TRIAL OF CARBOPLATIN AND NAVELEINE~ IN ADVANCED NON SMALL CELL LUNG CANCER (NSCLC). J Crawford, MA O’Rourke, J. Hohnekerand 5. Burman and supported bv Burrouahs WellcomeCo. RTP, NC.

The primary objectwe of the Phase I portmn of this trial was to determine the maximum tolerated dose (MTD) of Navelbine admimstered with Carboplatin to chemotherapy naive patients with advanced NSCLC (stage IV or recurrent disease after prior surgery or radiation therapy) The goal was to achieve a standard Phase II dose of Navelbine at 30 mg/mz intravenously weekly in addition to a fixed dose of Carboplatln determined by the Calvert formula to achieve an AUC of 7 once a month The MTD was defined as the highest dose at which less than half of the patients developed Grade Ill or IV non-hematologic toxuty, Grade IV thrombocytopenia, febrile neutropenia, or failed to recewe full dose chemotherapy on time through day 29. The primary ObJeCtlve of the Phase II portion of the trial was to examme the actwity of the combmatton of Carboplatin and Navelbinewhen admlnistered at the maximum tolerated dose. Secondary objectives of the trml were to assess expected and novel toxicities from the combination and to evaluate the efficacy of G-CSF support to reduce neutropenia and to maintain dose-Intensity in Datients who develooed Grade Ill neutrooenia in orevlous cvclcs of ireatment.

Cohorts of five patients were treated with CarhoplatIn wth weekly Navelbine at 0. 15 malmz. 22.5 molm2 or 30 molm2. lncreaslno myelotoricity,‘partic~larl~ neutr6penia. war seen wth increa<ng doses of Navelbine. However, with the adjunctive use of G-CSF, the MTD was not reached even in the cohort treated with Navelbine at 30 mg/mz This cohort has now been expanded in the Phase II trial which 15 currently completing accrual

In the Phase I portion for the initial twenty-two patients evaluable on this trial, there has been one septic death and one patlent who was removed from study after one cycle because of neurotoxlcity SIX of the first twenty-two patientsachieved a partial response, and surwval 15 favorable cornoared to our previous trial of Navelblne alone If this data IS confIrmed in the final anal&s of the Phase II port~on of the study, Carboplatin and Navelbine with G-CSF support warr~ntr further evaluation I” Stage Ill disease, as well asstudIes of further dose Intensillcdtion

464

EXTENDED ORAL ETOPOSIDE (E) AND ORAL CYCLOPHOSPHAMIDE ICI FOR LUNG CANCER. S.M. Grunberg, J. Crowley, R. Livingston. Southwest Oncology Group, San Antonio, Texas, USA

To take advantage of the schedule dependence of E and the ease of administration of an all oral regimen, we have initiated a series of studies of oral E and oral C given Days 1-14 every 28 days. In the first study, patients (pts) with Stage IV non-small cell lung cancer received E 50 mglm2 per day and C 50 mglm’ per day. 64 eligible pts received 192 cycles (median 2; range l-l 5) of E and C. 2 pts (3%) had Complete Response and 6 pts (9%) had Partial Response. The most common toxicities were anemia (41 pts), leukopenia (33 pts), alopecia 132 pts), and nausea (28 pts). Median survival was 6 months and 1 year survival rate was 26%. comparable to more intensive regimens. In an ongoing study, pts with poor prognosis (low albumin or poor performance status) extensive disease small cell lung cancer are receiving E 50 mg per day and C 50 mg per day. The lower fixed doses were chosen to compensate for the poorer tolerance of therapy expected in this patient population. Limited pharmacokinetic sampling in this study will allow creation of an algorithm to predict severe myelosuppression early in a course of extended oral E. Extended oral regimens of E and C are well tolerated and can serve as a basis for more complex outpatient regimens.